Method of producing degradation products of certain steroid compounds



Patented Nov. 7-, 1944 METHOD or monuomo mama-non raonugrs or cam-am s'rnnom oom- POUND Jacob Rosin, at. York, N. x.

N Drawing. Application April 18, 1944,

Serial No. 531,652

Claims. (01. zoo-397.3)

My invention relates to chromic steroid compounds, and the method of their production and use in connection with the formation of steroid degradation products. 'The present application is a continuation in part of my application Serial No. 498,589, filed August 13,1943.

Steroid degradation products are widely used in the manufacture of synthetic sex hormones and other organic compounds, having a great many pharmacological applications. The presently known methods of producing the synthetic sex hormones, while eflective, are relatively uncertain, expensive, complicated and wasteful of raw materials. With my method, I am enabled to produce intermediate compounds, chromic steroids, from which the production 01' the ultimate degradation products is achieved easily, quickly, positively, at much less expense and with greater yields than heretofore.

The old method of achieving the sterol deg-, radation products, such as deydroandrosterone,

progesterone, pregnenolone, androstendione, and

other ketones or acid derivatives, are all based onthe splittingoif of the sidechain of the sterols by means of direct oxidation. by an oxidative agent capable of splitting oil a carbon-to-carbon bond. These methods involve reacting the sterolcontaining compounds with the oxidant in the presence of acetic acid, either as a solvent, or as a part of a mixture of solvents. Hexavalent chromium compounds, as chromium trioxide, or others, are the most commonly used oxidants. This method as disclosed in Carpmael, British Patent No. 449,379, dated June 22, 1936, and in corresponding patents in other countries.

All of these direct oxidation methods are 'acetyl group;

hydroxyl groups. If these as by bromination and the yields will be even ring of the sterols will protected 3 position, at is attached. By the are not safegua ded, acetylation respectively, the A be split oil at the unwhich the hydroxyl group old methods, the best procedure for obtaining progesterone, ior example, would be by detouring over pregnenolone acetate and then, after hydrolization, to split oil! the bromination, to protect the double bond; oxidation and dehromination, to transform same into progesterone. Other disadvantages in the methods are the problems presented in the removal of the solvent and the identification and isolation of the degradation products.

With my method, I either overcome or avoid all of these disadvantages by departing entirely from the old theories. the, sterol-containing'-products into reaction with chromium oxychlorideunder conditions by which the chromium -oxychloride does not act as an oxidative agent to split oil the side chain, but as a material to form, with the sterols, a new series of metalorganic compounds-chromium oxychloride sterols-in which chromium is still hexavalent. Chromium oxychloride steroids have never before been produced and isolated. From the metalorganic compounds formed by my method, I can produce-the ultimate degradation products simply and easily.

The main object or my invention, therefore, is

' the provision of a methodof treating raw sterolsfaulty in several respects. The yield is rather small because the degradation products continue to be oxidizedin the presence of the raw materials which have not yet entered into the reaction. The oxidant and the sterol-containing materials are not particularly soluble in acetic acid, so that relatively large amounts-of acetic acid must be employed. Further, itfis diillcu-lt to prevent the splitting oil of the whole side chain, resulting in the formation of ketones of the C19 series, and the ,.more desirable ketones of the C21 series can be obtained only as byproducts in very small yields. Thus, pregnenolone and progesterone, for instance, as ketonesv of the C21 series are very difllcult and expensive to produce. When cholesterol is used as the starting material, almost the entire ketone i'raction will consist of the Cu series. Of course, when the much more expensive stigmasterol is used as the starting material, the yield in ketones of the C21 series will be somewhat better, but

' still very small, ketones of the C10 series still being the main resultant product. Another disadvantage is the necessity for protecting, during 60 steroid compounds to the oxidation, both the double bond and the containing material as to produce sterols degradation products with intact cyclopentano polyhydro-phenathrene nucleus.

Associated with this obiect,'-as another obj ect of my invention, is the production and isolation of intermediary products from sterol compounds, which may thereafter be treated to yield sterol degradation products;

Another object of my invention is the provision of a method of producing and isolating intermediary steroid compounds.

Another object of my invention is the produc-- tion of chromium oxychloride-steroids in isolatable 1' orm'.

Another object of my invention is the provision of a method of producing and isolating chromium.

oxychloride-steroids.

Still another object of my invention is the provision of a method of precipitating chromium oxychloride-steroids from sterol compounds. in isolatable form.

Still another object vision of a method oxychloride-steroids pounds with chromium oxychloride.

ofmy invention is the proor precipitating chromium Still another object or my invention is the provision of a method of treating interm dation products.

Broadly speaking,-I bring by reaction of sterol comyield ultimate sterol degra-' Still another object of my invention is the provision of a method of decomposing chromium oxychloride-steroids to produce steroid degradation products.

Still another object of my invention is the provision or a methodof decomposing chromium oxychloride-steroids by water, aqueous solutions, or organic acids and other organic compounds capable of efiecting the decomposition, to produce steroid degradation products.

Depending on conditions (to be detailed below), one or more molecules oi chromium oxychloride are permitted. to enter into the sterol molecule, care being taken to prevent the decomposition of the chromium oxychloride sterols during the reaction. Thus, in my process, there is substantially quantitative yield oi chromium oxychloride steroids, plus unchanged raw material when the reactions are not' completely carried through. Once obtained, however, my metal-organic compounds, the chromium oxychloride steriods, are protected against further reaction since they are very resistant to chromium oxychloride. and the addition of more chromium oxychloride would merely result in a reaction between unchanged sterol containing raw material and the chromium oxychloride, and not between the chromium oxychloride and the already-formed chromium oxychloride sterols. In other words, no oxidative degradation takes place during this reaction, which may occur either by precipitation or by direct combination.

Once I have formed the metalorganic compounds, the chromium oxychloride steriods, I then subject them to decomposition by water, by organic acids, or by other suitable non-oxidative agents. During this subsequent decomposition, the chromium salts are split oil and simultaneously the degradation of the side chain is effected. There is present, in this stage of my process. no oxidative agent, and the degradation is effected by the autooxidation of every chromium oxychloride sterol molecule, which contains oxygen within itself. No overoxidation is possible, for every molecule is subjected to degradation only as far or as long as its own oxygen supply lasts, and there is no other or outside oxidative agent to attack the ultimate products and they are thereby protected.

My method, therefore, comprises the non-oxidative formation of chromic steroid compounds and their subsequent autooxidative degradation in the absence of any outside oxidant;

I have, with my method, overcome or obviated all the disadvantages of the old processes. I can now control the nature and extent of the reac tion, all the way from the formation of the ehromic steroids to the degradation products. Also, I have eliminated or substantially reduced the use of solvents in the interactions between the sterol-containing material and the hexavalent chromium.

Within the above general statement of procedure, I can regulate the extent and nature of the degradation in several ways. (1) By the amount of chromium oxychloride molecules introduced into the sterol molecule to form the chromium oxychloride steroid desired. The amount is determined by the augmentation in weight of the chromium oxychloride sterol obtained as compared to the weight of sterol used. (2) By the manner in which the sterol-containing compound is reacted with the chromium oxychloride. For partial degradation of the side chain, as when ketones of the C21 series are to be obtained,

' internal or auto-oxidizing effect is more limited than when organic acids are used, because in water a part of the chromium salts split off still retain their hexavalency, whereas in organic acids only salts of trivalent chromium are split 01?. (4) By varying the concentration of the decomposingmaterial. Thus, a very violent decomposition, and even an explosion, may be achieved if only a very small amount of water is use It is obvious, therefore, that depending on the particular degradation product desired, and the raw material used, the conditions above referred to may be varied, but the rationale of my method remains constant; there is no direct oxidation by an outside oxldatlve agent. Instead, I form and isolate the chromium oxychloride steroid compounds, wherein chromium maintains intact its hexavalen-cy, after which I decompose the chromium oxychloride sterols without using any outside oxidative agent.

Example I As .one example of my process, one thousand (1,000) grams of cholesterol dibromide may be spread in thin layers over the shelves of a cabinet, covering a relatively large surface area. Wide mouthed dishes containing chromium oxychloride are disposed inside the cabinets, on supports spaced over the shelves. The cabinet is then closed and sealed against the atmosphere with paraffin. The cabinet is opened after six hours and the chromium oxychloride sterol formed on the shelves may be poured into ten litres of water. The decomposition starts immediately; the chromium salts go into solution and the steroid degradation compounds and unchanged raw material precipitate out. They are filtered, washed and dried. The precipitate is then treated with three (3) litres of methanol. All the degradation products go into solution, whereas most of the unchanged cholesterol dibromide remains undissolved and is readily separated by filtration. Five hundred and fifty (550) grams of cholesterol dibromide may thus be recovered and can be used for the next batch. The methanol filtrate is evaporated in vacuum to dryness and the residue subjected to the usual debromination and purification procedure. The yield in this example is about one (1) gram of progesterone.

If desired, a further amount of unchanged cholesterol dibromide maybe recovered by a second recrystallization of the methanol filtrate residue, so that the percentage of yield may be increased.

Example II on supports above the shelves? The'aibl'iiet is then closed and sealed against the atmosphere with paramn, and kept sealed at room temperatures ior twenty-four (24) hours. The cabinet may then be opened and the chrome steroid compound removed, as by scraping, from the shelves. The material is y. p wdery and of light brown color and its weight is equal to 200% to 210% of the cholesterol di'bromide used. No

calorific effect was observed during the formation of this product. The weight of the chromium oxychloride is correspondingly reduced.

As is well known, the formulae ofeven the most simple organic compounds of chromium oxychloride are open to question and discussion, and it is impossible to establish the exact structure and formulae of the so much complicated metalorganic chromium oxychloride sterols. However, the general formula may be given thusly:

with the letter R representing the steroid compound in question. Upon examination, this brown material will be found to consist, as in the first example of my process, of chromium oxychloride sterols. It is relatively insoluble in carbon tetrachloride, but can be easily decomposed by water into carbon tetrachloride-soluble: sterol compounds and into inorganic chromium compounds.

The chromic steroid compound having thus been isolated, it may thereafter be reduced to yield the ultimate sterol degradation product, progesterone, and others, by decomposing same. For instance, the product achieved in the above example, is poured into ten litres of glacial acetic acid under agitation, as by stirring or otherwise. The product first starts, dissolving with brownish color, but shortly after the decomposition starts, the solution turns green and bromide and the chromium oxychloride are very soluble in the halogenated hydrocarbon solvents and a relatively small amount of the solvent will sufiice to support the desired reaction. Atter a while, a brown precipitate will be formed. The solvent may be removed easily as by filtration in a filter press, by distillation, or merely per mitted to evaporate. Preferably, of course, it is collected for re-use in further batches.

" oxychloride steroids, and the final steps may be practiced as outlined above in Examples I and II.

Within my method, other sterols as sitosterol, stigmasterol and other steroid compounds may be used instead of cholesterol. Also, within my method, other solutions, etc., may be used instead of water, acids or alkalis, to provoke the ultimate degradation decomposition reaction of the chromium oxychloride steroids into degradation products and inorganic chromium compounds.

It is seen, therefore, that my method is far simpler than the old methods, it is easier to practice, and presents'no problems in technique. It is cheaper, consumes less time, uses less raw materials and results in increased yields of ultimate degradation products. The process is much more controllable and the specific end product desired the temperature. rises to about -to 50 0., and

any undissolved portion of the material goes into solution. The solution is permitted to remain quiescent for twenty-four (24') hours to complete the decomposition and the debromination may be carried out with zinc powder directly in the same solution, followed by the usual extraction and purification.

The cholestenone-free ketone fraction, upon extraction with petroleum ether and evaporation of the extract to dryness, yields a product containing 25% to 30% of progesterone which is practically free of any androgenic activity. The yield in progesterone is three (3) grams.

The fraction separated from the progesterone as a petroleum ether-insoluble fraction, has androgenic activity.

Example III Cholesterol acetate dibromide is used as the starting material instead of cholesterol dibromide, and the procedures of Examples I and II are followed and will yield pregnenolone acetate instead of progesterone.

Example 1V When it is desired to achieve degradation products as dehydroandrosterone, androstiendione, etc., by splitting ofl the whole side chain, the formation of chromic oxychloride sterols may be carried out in proper solvents. I dissolve 28.5 grams of cholesterol acetate dibromide in 50 cc. of carbon tetrachloride, chloroform or any similar halogenated hydrocarbon. I thereafter add 10 cc. of chromium oxychloride to the solution and agitate the same under control to prevent overheating. Boththe cholesterol acetate diis achieved with much greater certainty than heretofore.

Having now described my invention, what I claim and desire to secure by Letters Patent is:

1. The method of producing degradation products of steroid compounds having an aliphatic side chain at the l'l-position which comprises forming and isolating chromium oxychloride compounds of such steroids by subjecting such steroids to the action of chromium oxychloride vapors and thereafter decomposing these compoundsof such steroids into steroid degradation products and chromium compounds.

2. The method of claim 1, in which the steroids are decomposed by the action of water.

3. The method of claim 1, in which the steroids are decomposed by the action of aqueous solutions.

4. The method of claim 1, in which the steroids are decomposed by the action of acids.

5. The method of claim 1, in which the steroids are decomposed by the action of a non-oxidative organic solvent. Y

6. The method of producing progesterone which comprises reacting chromium oxychloride vapors with steroids having an aliphatic side chain at the 17-position and methyl groups at the .10- and l3-positions and having a protected double bond in the nucleus and an unprotected free hydroxyl group at the 3-position, to form and isolate chromium oxychloride compounds of such steroids, thereafter decomposing same into steroid degradation products and chromium compounds. and then dehalogenating the degradation products.

' oids are decomposed by the action of a non-oxidative organic solvent.

' JACOB ROSIN.

The brown precipitataes will consist of the chromium 

